This invention relates to a salt of S(+)-ibuprofen, to its anti-inflammatory, anti-pyretic and analgesic activity, to pharmaceutical compositions containing the salt, to its use as an intermediate in a process to prepare S(+)-ibuprofen of high enantiomeric purity and to a novel form of the salt.
(xc2x1)-2-(4-Isobutylphenyl)propionic acid, ibuprofen, is a potent and well tolerated anti-inflammatory, analgesic and anti-pyretic compound. The racemic mixture consists of two enantiomers, namely S(+)-2-(4-isobutylphenyl)propionic acid or S(+)-ibuprofen and R(xe2x88x92)-2-(4-isobutylphenyl)propionic acid or R(xe2x88x92)-ibuprofen. It is known that S(+)-ibuprofen is the active agent and that R(xe2x88x92)-ibuprofen is partially converted into S(+)-ibuprofen in humans. The drug has been previously marketed as the racemic mixture, however, in certain circumstances it may be advantageous to administer S(+)-ibuprofen. Problems arise, however, when attempting to formulate S(+)-ibuprofen into pharmaceutical compositions due to its low melting point of 51xc2x0 C.
DE 3922441 considers the formulation problems associated with the low melting point of S(+)-ibuprofen and proposes a solution to the problem by using the calcium salt of S(+)-ibuprofen on its own or in admixture with a compound selected from the group comprising the sodium-, potassium- or ammonium- S(+)-ibuprofen salt, ibuprofen or S-(+)-ibuprofen. It is disclosed that the pharmaceutical composition must contain the calcium salt as an essential component as alkali metal salts of S(+)-ibuprofen per se, for example the sodium salt, are too hygroscopic to allow satisfactory tabletting.
We have now prepared and characterised the sodium salt of S(+)-ibuprofen and surprisingly we have found that it possesses advantageous formulation properties. The sodium salt of S(+)-ibuprofen has a negative optical rotation of xe2x88x924.3xc2x0 and is thus correctly named as S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate.
The preparation of the sodium salt of S(+)-ibuprofen in anhydrous form for use as a base, as an alternative to the use of pyridine, in a process to racemise S(+)-ibuprofen, is described in U.S. Pat. No. 4,946,997. In this reference no details are given of the physical properties of the material obtained and there is no suggestion that the material is suitable for pharmaceutical use.
The administration of S(+)-ibuprofen as a solution in dilute sodium hydroxide to a normal subject in a volunteer study has been reported (Lee et al, J. Pharm Sci. Vol. 73, No. 11, 1984, pp 1542-44). However, the taste of such a preparation would be unacceptable to the vast majority of patients.
The present invention provides pharmaceutical compositions comprising S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of at least 90%, together with a pharmaceutically acceptable carrier, with the exception of (a) compositions consisting of a solution of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate in water with no additional pharmaceutical excipient and (b) compositions comprising the calcium salt of S(+)-ibuprofen.
S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate possesses a number of formulation advantages over S(+)-ibuprofen. S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate may be easily compressed into tablets even on long compressing runs during which the temperature of the tablet tooling will rise. Under similar circumstances S(+)-ibuprofen would tend to stick and generally display poor flow characteristics. S(xe2x88x92)sodium 2-(4-isobutylphenyl)-propionate may also be easily milled to the most appropriate particle size. These advantages would not be expected from consideration of the prior art (DE 3922441) referred to earlier.
The high melting point of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate, 220-222xc2x0 C., allows higher temperatures to be used in drying intermediates in formulation processes, for example granules, compared to the corresponding intermediates containing S(+)-ibuprofen. The high melting point also gives increased physical stability to final formulations containing S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate during storage for example in hot climates compared to final formulations containing S(+)-ibuprofen which may deteriorate when stored at temperatures close to the melting point of S(+)-ibuprofen.
S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate has a higher water solubility than S(+)-ibuprofen and is thus very useful in the formulation of pharmaceutical compositions containing water. Such compositions may be formulated to have a bright, clear, aesthetically-appealing appearance.
An additional formulation advantage is that S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate will resist esterification with excipients which contain a hydroxyl group for example mono-, di-, tri- or poly-hydric alcohols. For example this is a problem encountered when formulating S(+)-ibuprofen with liquid fill excipients, for example, esterified natural vegetable oils which may contain alcohols.
The enantiomeric purity of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate used in the pharmaceutical compositions of the invention is in the range of 90-100%. Preferably the enantiomeric purity of the S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate used greater than 95%, more preferably the enantiomeric purity is greater than 98% and most preferably the enantiomeric purity is greater than 99%. In an especially preferred embodiment of the present invention the enantiomeric purity is greater than 99.5% e.g. greater than 99.9%. We have found that S(xe2x88x92)sodium 1-(4-isobutylphenyl)-propionate can exist in the form of a stable dihydrate which is a novel and valuable compound for use in preparing pharmaceutical compositions. In the following detailed description of compositions of the invention the term S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate includes the anhydrous form and hydrated forms. Preferably the dihydrate is used.
S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate dihydrate may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
In therapeutic use, S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate may be administered orally, rectally, parenterally or topically, preferably orally or topically. Suitably the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions of the invention may contain 1-99% by weight of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate. The compositions of the invention are generally prepared in unit dosage form. Preferably the unit dosage of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate is in the range of 10-1200 mg in a precalculated amount to provide doses which are equivalent by weight to doses of for example 100 mg, 200 mg, 400 mg or 800 mg of S(+)-ibuprofen.
Solid compositions for oral administration are preferred compositions of the invention and there are known pharmaceutical forms for such administration, for example tablets and capsules. Suitably tablets may be prepared by mixing S(xe2x88x92)sodium 2-(4-isobutylphenyl)-propionate with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, for example magnesium stearate, and tableting the mixture by known methods. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing S(xe2x88x92)sodium 2-(4-isobutylphenyl)-propionate with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The tablets may be formulated in a manner known to those skilled in the art so as to give a controlled release of the compound of the present invention. Other compositions for oral administration include oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
Preferably, a solid composition comprises a) 10-99% S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate; b) 1-90% of a diluent and c) 0.1-10% of a lubricating agent, d) 0.1-15% of a disintegrating agent and optionally e) 0.1-15% of a binder. Optionally 0.1-10% of a flow aid may be added.
Preferably the diluent includes lactose, calcium phosphate, dextrin, microcrystalline cellulose, sucrose, starch, calcium sulphate or mixtures thereof. More preferably the diluent is lactose or calcium phosphate. Preferably the lubricating agent includes magnesium stearate, stearic acid, calcium stearate or mixtures thereof. More preferably the lubricating agent is magnesium stearate or stearic acid. Preferably the disintegrating agent includes microcrystalline cellulose, maize starch, sodium starch glycollate, low substituted hydroxypropyl cellulose, alginic acid or croscarmellose sodium or mixtures thereof. Preferably the binder includes polyvinyl pyrrolidone, gelatin, hydroxypropylmethyl cellulose, starch or mixtures thereof. More preferably the binder is polyvinylpyrrolidone. Suitable flow aids include talc and colloidal silicon dioxide. It will be appreciated by those skilled in the art that a particular excipient may perform more than one function for example maize starch may act as a diluent, a binder or as a disintegrating agent.
Controlled release forms of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate include rapid release formulations such as soluble granules or melt filled fast release capsules, delayed release formulations such as tablets provided with enteric coatings, for example, of cellulose acetate phthalate and, in particular, sustained release formulations. Numerous types of sustained release formulations are known to those skilled in the art. Typically, S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate may be encapsulated within a release retarding coating, for example, a copolymer of cellulose ether and acrylate, or may be bound to small particles such as, for example, ion exchange resin beads. Alternatively, S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate may be incorporated into a matrix containing a release retarding agent such as a hydrophilic gum e.g. xanthan gum, a cellulose derivative e.g. hydroxypropyl methylcellulose, or a polysaccharide, wax or plastics material. Such techniques may provide sustained blood levels of S(+)-ibuprofen by controlling, for example, erosion, swelling, disintegration and dissolution of the composition within the gastrointestinal tract.
Liquid fill compositions for example viscous liquid fills, liquid paste fills or thixotropic liquid fills are also suitable for oral administration. Melt filled compositions may be obtained by mixing S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate with certain esters of natural vegetable oil fatty acids, for example, the Gelucire (Trademark) range available from Gattefosse to provide a variety of release rates. Suitably a melt-filled capsule comprises a) 10-80% S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate and b) 20-90% of a fatty acid ester excipient which comprises one or more polyol esters and triglycerides of natural vegetable oil fatty acids.
Solid compositions designed to effervesce when added to water to form an effervescent solution or suspension are also suitable for oral administration.
Suitably an effervescent composition comprises a) 1-50% of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate and b) a pharmaceutically acceptable effervescent couple. Such a composition may be presented in the form of tablets or granules. Although S(xe2x88x92)sodium 2-(4-isobutylphenyl)-proionate may have advantageous organoleptic properties compared to the sodium salt of racemic ibuprofen preferably the effervescent compositions additionally comprise a taste masking component for example a sweetener, a flavouring agent, arginine, sodium carbonate or sodium bicarbonate.
Solid non-effervescent compositions are preferred compositions of the present invention. Preferably such compositions comprise S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate as the dihydrate.
Preferably oral liquid compositions comprise a) 0.1-10% S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate b) 1-50% of a diluent c) water to 100%. Optionally the composition may contain alcohol and/or include a preservative. Suitable diluents include sweetening agents for example sorbitol, xylitol, sucrose, or LYCASIN(copyright) (registered trademark of Roquette). Flavourings or other taste-masking agents known to those skilled in the art for example saccharin, sodium saccharin may be added. The use of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate in aqueous liquid compositions is particularly advantageous as it provides clear, homogeneous, bright formulations which are aesthetically appealing to the consumer in addition to the beneficial pharmacological effect provided.
Compositions for topical administration are also preferred compositions of the invention. Suitably the S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A suitable cream may be prepared by incorporating S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate in a topical vehicle such as petrolatum and/or light liquid paraffin, dispersed in an aqueous medium using surfactants. An ointment may be prepared by mixing S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate with a topical vehicle such as a mineral oil, petrolatum and/or a wax e.g. paraffin wax or beeswax. A gel may be prepared by mixing S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate with a topical vehicle comprising a gelling agent e.g. basified Carbomer BP, in the presence of water.
Suitable topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally for example in a patch or poultice. A suitable transdermal composition may be prepared by mixing S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate with a topical vehicle, such as described above, together with a potential transdermal accelerant such as dimethyl sulphoxide, propylene glycol or peppermint oil.
Semi-solid compositions are preferred for topical use for example compositions in the form of a cream, an ointment or a gel. Suitable gels comprise a) 1-15% S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate; b) 1-20% of a gelling agent c) 0.01-10% of a preservative and d) water to 100%. Preferably the gelling agent comprises 0.1-10% of a carbomer and a neutralising agent. It is a particular advantage of the present invention that as a result of the high water solubility of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate clear gels are obtained which have an acceptable cosmetic appearance and texture in addition to their pharmacological actvity.
A suitable cream comprises a) 1-15% S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate; b) 5-40% of an oily phase; c) 5-15% of an emulsifier; d) 30-85% of water. Suitable oily phases comprise petrolatum and/or light liquid paraffin.
Alternatively, S(xe2x88x92)sodium 2-(4-isobutylphenyl)-propionate may be distributed in a base comprising a) 10-40% of a self-emulsifying base b) 60-90% of water to form a cream. LABRAFILL and GELOT (both tradenames of Gattefosse) are examples of self-emulsifying bases.
A suitable ointment comprises a) 1-15% S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate and b) a topical vehicle to 100%. Suitable topical vehicles include mineral oil, petrolatum and/or a wax.
Compositions of the invention suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with polyethylene glycol bases or semi-synthetic glycerides. Preferably the composition in the form of a suppository comprises 10-30% S(xe2x88x92)sodium 2-(4-isobutylphenyl)-propionate and 70-90% of a carrier wherein the carrier is selected from a base which comprises polyethylene glycol or a semi-synthetic glyceride.
Compositions of the invention suitable for parenteral administration are known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
In some formulations it may be beneficial to use S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate in the form of particles of very small size, for example as obtained by fluid energy milling.
In the compositions of the present invention the S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate may, if desired, be associated with other compatible pharmacologically active ingredients and/or enhancing agents. Thus, for example, S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate may be combined with any ingredient commonly used in a cough or cold remedy, for example, an antihistamine, caffeine or another xanthine derivative, a cough suppressant, a decongestant, an expectorant, a muscle relaxant, or combinations thereof.
Suitable antihistamines which are preferably non-sedating include acrivastine, astemizole, azatadine, azelastine, bromodiphenhyrdramine, brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, ebastine, ketotifen, lodoxamide, loratidine, levocubastine, mequitazine, oxatomide, phenindamine, phenyltoloxamine, pyrilamine, setastine, tazifylline, temelastine, terfenadine, tripelennamine or triprolidine. Suitable cough suppressants include caramiphen, codeine or dextromethorphan. Suitable decongestants include pseudoephedrine, phenylpropanolamine and phenylephrine. Suitable expectorants include guaifensin, potassium citrate, potassium guaiacolsulphonate, potassium sulphate and terpin hydrate.
S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate is an anti-inflammatory, analgesic and anti-pyretic agent. It is, therefore, indicated for use in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, seronegative arthropathies, periarticular disorders and soft tissue injuries. S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate may also be used in the treatment of postoperative pain, postpartum pain, dental pain, dysmenorrhoea,headache, musculoskeletal pain or the pain or discomfort associated with the following: respiratory infections, colds or influenza, gout or morning stiffness.
In another aspect the present invention provides a pharmaceutical composition comprising S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of at least 90% together with a pharmaceutically acceptable carrier for use in the treatment of inflammation, pain and pyrexia. Preferably the S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate in present as the dihydrate.
In a further aspect the present invention provides the use of a pharmaceutical composition comprising S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of at least 90% together with a pharmaceutically acceptable carrier for the manufacture of a medicament for use as an antiinflammatory, analgesic and anti-pyretic agent. Preferably the S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate in present as the dihydrate.
It will be appreciated that the present invention provides a method of treating inflammation, pain and pyrexia by administration of a pharmaceutical composition comprising S(xe2x88x92)sodium 2-(4-isobutylphenyl)-propionate having an enantiomeric purity of at least 90% together with a pharmaceutically acceptable carrier to a mammal, e.g. a human, in need thereof. Preferably the S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate in present as the dihydrate.
S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate may be absorbed more quickly from the gastrointestinal tract in humans than S(+)-ibuprofen thus giving therapeutically acceptable plasma levels in a shorter period of time. This effect offers the possibility of eliciting an onsetxe2x80x94hastened and/or enhanced therapeutic response, by use of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate compared to S(+)-ibuprofen, which is especially important in cases where analgesia is required, for example,. in headache or dental pain. Thus the present invention includes a method of eliciting an onset-hastened and/or enhanced analgesic response compared to the use of an equivalent dose of S(+)-ibuprofen in a mammal, e.g. a human, comprising the administration of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate to a mammal in need thereof.
This surprising effect occurs not only when S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate is administered in solution but also when administered in other formulations, for example, solid formulations for oral use (for example tablets or capsules) or suppositories.
In another aspect the present invention provides a method of preparing a pharmaceutical composition comprising S(xe2x88x92)-sodium 2-(4-isobutylphenyl)propionate together with a diluent or carrier characterised in that S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate dihydrate is used as the source of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate.
In a further aspect the present invention provides a process to prepare a pharmaceutical composition comprising S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of at least 90% together with a pharmaceutically acceptable carrier comprising combining S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of at least 90% in solid form with a pharmaceutically acceptable carrier and formulating into a dosage form.
A preferred process for preparing a solid composition in tablet form comprises combining 10-90% of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of at least 90% with 1-90% of a diluent, optionally adding other pharmaceutically acceptable excipients selected from lubricating agents, disintegrating agents, binders, flow aids, oils, fats and waxes, mixing the ingredients with one another to form a uniform mixture, and compressing the mixture thus obtained to form tablets which may be optionally coated with a film coat or a sugar-coat.
Processes for the preparation of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate will now be described. These processes form another aspect of the present invention. In the following description of these processes the term S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate includes the anhydrous form and hydrated forms for example the dihydrate.
S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate may be prepared by neutralising S(+)-2-(4-isobutylphenyl)propionic acid with a sodium-containing base. It would be expected that in order to prepare S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate in an enantiomerically pure form, for example greater than 90%, then the S(+)-2-(4-isobutylphenyl)propionic acid employed would be required to be greater than 90%. While this procedure may be used, it is time-consuming and costly to prepare S(+)-2-(4-isobutylphenyl)propionic acid of greater than 90% enantiomeric purity. Typically racemic ibuprofen is resolved using S(xe2x88x92)-1-phenylethylamine as described in the Journal of Pharmaceutical Sciences, 1976, page 26. The intermediate S(xe2x88x92)-1-phenylethylammonium S(+)-2-(4-isobutylphenyl)propionate salt requires several recrystallisations to raise the enantiomeric purity of the S(+)-ibuprofen produced, after hydrolysis of the salt, to above 90%. The amine employed is expensive and in theory the yield of S(+)-ibuprofen obtained cannot exceed 50%. The unwanted R(xe2x88x92)-ibuprofen may be racemised and the resolution procedure repeated to produce more S(+)-ibuprofen but overall the whole process is costly in terms of manpower, materials and plant equipment.
It is known that ibuprofen crystallises as a racemic compound rather than a mixture of enantiomers and that consequently preferential crystallisation is not an efficient process for the removal of small amounts of R(xe2x88x92)-ibuprofen from a sample of S(+)-ibuprofen.
Unexpectedly in preparing solid S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate we have discovered that this salt may be purified enantiomerically by crystallisation and that this surprising property may be utilised industrially to provide a simple, efficient and very cheap process to prepare S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate of high enantiomeric purity and to provide a process to prepare S(+)-ibuprofen of high enantiomeric purity. The process may be adapted to provide R(+)sodium 2-(4-isobutylphenyl)propionate of high enantiomeric purity and optionally to prepare R(xe2x88x92)-ibuprofen of high enantiomeric purity.
Accordingly, the present invention provides a process for preparing a sodium salt of a desired enantiomer of 2-(4-isobutylphenyl)propionic acid said sodium salt having an enantiomeric purity of greater than 90% that is 90-100% comprising the steps of:
a) neutralising 2-(4-isobutylphenyl)propionic acid containing 50% or more of the desired enantiomer with a sodium-containing base in the presence of a solvent system;
b) crystallising to produce the solid sodium salt of the desired enantiomer; and
c) separating said solid from the solvent system; and either
d) recrystallising said solid or
e) converting said solid into 2-(4-isobutylphenyl)propionic acid and repeating steps a, b and c.
This process is surprising since it is known in the art that pure enantiomers of arylpropionic acids may be racemised when heated in the presence of a base.
Suitably the 2-(4-isobutylphenyl)propionic acid used contains 70% or more of the desired enantiomer, preferably 80% or more of the desired enantiomer and more preferably 85% or more of the desired enantiomer.
In a more preferred embodiment the present invention provides a process for preparing S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of greater than 90% comprising the steps of:
a) neutralising 2-(4-isobutylphenyl)propionic acid containing 85% or more of the S(+)-enantiomer with a sodium-containing base in the presence of a solvent system;
b) crystallising to produce solid S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate and
c) separating said solid from the solvent system.
Optionally the S(xe2x88x92)sodium 2-(4-isobutylphenyl-propionate may be recrystallised. Optionally, the S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate may be acidified to produce S(+)-2-(4-isobutylphenyl)propionic acid of higher enantiomeric purity than the acid used as starting material.
Preferably the process provides S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of greater than 95%. More preferably the process provides S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of greater than 98%. Most preferably the process provides S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of greater than 99%. In an especially preferred process the enantiomeric purity is greater than 99.5% e.g. greater than 99.9%.
In a most preferred embodiment the present invention provides a process for preparing S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric of greater than 99% comprising the steps of:
a) neutralising 2-(4-isobutylphenyl)propionic acid containing 95% or more of the S(+)-enantiomer with a sodium-containing base in the presence of a solvent system;
b) crystallising to produce solid S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate and
c) separating said solid from the solvent system.
2-(4-Isobutylphenyl)propionic acid containing 50% of a desired enantiomer i.e. racemic ibuprofen may be prepared by methods known to those skilled in the art. 2-(4-Isobutylphenyl)propionic acid containing more than 50% of a desired enantiomer for example 70%, 80%, 85%, 90%, 95% and 98% may be prepared by the partial resolution of racemic ibuprofen via salt formation with an optionally active amine for example S(xe2x88x92)-1-phenylethylamine followed by separation and hydrolysis as is well known in the art. Alternatively starting material for use in the process containing more than 50% of a desired enantiomer 2-(4-isobutylphenyl)propionic acid may be prepared by asymmetric synthesis using chemical techniques for example asymmetric hydrogenation, or biochemical techniques, for example stereoselective enzymatic ester hydrolysis.
The term neutralisation as used above means that substantially a molar equivalent of base is used within acceptable experimental error of around 10%. It will be appreciated by a person skilled in the art that the sodium salt of 2-(4-isobutylphenyl)propionic acid will give a pH value of greater than 7 in aqueous solution. In practice we have found that best results are achieved by neutralisation in the range 90-98% for example 96% of the calculated amount of 2-(4-isobutylphenyl)propionic acid and then measuring the pH of the solution to confirm that it is into the range of pH 8-9.9 prior to crystallisation. If necessary the pH may be adjusted to the required value by the addition of more acid or base. It will be appreciated that if the solution is heated at a pH greater than 10 for any length of time that there is a possibility of racemisation occurring.
The formation of the sodium salt of S(+)-2-(4-isobutylphenyl)propionic acid may be carried out in numerous ways. Typically the acid is reacted with an equivalent of a sodium-containing base in a solvent system. Suitable sodium-containing bases are sodium hydroxide, sodium carbonate, sodium bicarbonate, a sodium alkoxide, for example sodium methoxide or sodium ethoxide, sodium hydride or sodamide. Preferably the sodium-containing base is sodium hydroxide or a sodium alkoxide. Most preferably the sodium-containing base is sodium hydroxide.
The solvent system employed depends on the sodium-containing base used and may be a single solvent or a mixture of solvents. The solvent system may contain water when a hydrolytically-stable, sodium-containing base is used, for example sodium hydroxide, or the solvent system may be substantially anhydrous when a hydrolytically-unstable, sodium-containing base, for example a sodium alkoxide or sodium hydride, is used. The purpose of the solvent system is to allow contact between the acid and sodium-containing base to permit formation of the sodium salt of the acid and to provide a medium from which this salt will crystallise or precipitate. Any solvent system in which these purposes are achieved may be used.
Suitably the solvent system contains water. When the solvent system employed contains water in at least twice the stoichiometric amount of the 2-(4-isobutylphenyl)propionic acid used as the starting material then the S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate initially obtained is in the dihydrate form which may be dried by heating, optionally under vacuum to produce the anhydrous form. When the solvent system employed is anhydrous the initially formed S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate is anhydrous.
Suitable solvent systems for hydrolytically-stable, sodium-containing bases are water or mixtures of water and at least one water-miscible organic solvent for example acetone or a C1-4 alcohol for example methanol, ethanol, propan-1-ol, propan-2-ol or butan-1-ol. Also suitable are mixtures of water and a partially water-miscible organic solvent for example methyl ethyl ketone. Preferably the solvent system comprises a mixture of water and acetone.
Alternatively the solvent system may comprise a mixture of water and a water-immiscible organic solvent in a two phase solvent system wherein the 2-(4-isobutylphenyl)propionic acid is dissolved in the organic phase and the base is dissolved in the aqueous phase. The mixture may be agitated for example by stirring or shaking to form the sodium salt of the acid in the aqueous layer. The sodium salt may be recovered from the aqueous layer, optionally after separating the two layers, by crystallisation optionally after the addition of a water miscible organic solvent, for example acetone. Suitable water-immiscible solvents are for example aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers or esters. Preferably the water immiscible solvent is toluene.
When a hydrolytically-unstable, sodium-containing base is employed for example a sodium alkoxide such as sodium methoxide, a suitable solvent system comprises a substantially anhydrous inert organic solvent, for example toluene or methanol, which is compatible with the base employed.
Suitably the formation of the sodium salt is carried out at a temperature in the range of 0-150xc2x0 C., although lower temperatures may be used, preferably in the range 5-120xc2x0 C. and most preferably in the range 10-80xc2x0 C. In a particularly preferred embodiment the formation of the sodium salt is carried out in the range from ambient temperature to 50xc2x0 C. at atmospheric pressure.
Suitably the crystallisation of the sodium salt is carried out at a temperature in the range between the boiling point of the solvent system employed and the freezing point of the solvent system. Suitably the crystallisation may be carried out at a temperature in the range from xe2x88x9250xc2x0 C. to +50xc2x0 C. , preferably in the range xe2x88x9220xc2x0 C. to ambient temperature and most preferably from xe2x88x9210xc2x0 C. to +10xc2x0 C. at atmospheric pressure. It will be appreciated by those skilled in the art that the crystal size of the product obtained, may be varied by adjusting the crystallisation temperature, and by varying the rate of cooling.
In a preferred process according to the present invention S(+)2-(4-isobutylphenyl)propionic acid is converted into the sodium salt by reaction with sodium hydroxide in the presence of a solvent system comprising a mixture of water and acetone. Suitably the process is carried out in the range 0-80xc2x0 C. , preferably between 40xc2x0 C. and 60xc2x0 C. Suitably the volume ratio of acetone to water is in the range from 50:1 to 1:10 preferably the ratio is in the range 20:1 to 1:1 and most preferably in the range 15:1 to 2:1.
The sodium salt may be crystallised from the solvent system by methods for encouraging crystallisation known to those skilled in the art. For example the solvent system may be cooled, concentrated, seeded with the desired material or diluted with a solvent in which the sodium salt is less soluble or any combination of these methods may be employed. Preferably the solvent system is selected so that the sodium salt crystallises immediately after it is formed or on cooling of the solvent system.
The crystallised sodium salt may be separated from the solvent system by methods known to those skilled in the art for example by filtration or centrifugation.
In another aspect the present invention provides a process for preparing a sodium salt of a desired enantiomer of 2-(4-isobutylphenyl)propionic acid said sodium salt having an enantiomeric purity of greater than 90% comprising the steps of:
a) dissolving sodium 2-(4-isobutylphenyl)propionate containing 50% or more of the desired enantiomer in a solvent to form a saturated solution;
b) seeding said solution with the desired enantiomer of sodium 2-(4-isobutylphenyl)propionate;
c) cooling said solution in a controlled manner to cause crystallisation of the solid sodium salt;
d) separating said solid sodium salt from the solvent;
e) repeating steps a to d until the desired level of enantiomeric purity is achieved.
The crystallisation mother liquors which contain a higher proportion of the undesired enantiomer may be racemised by known methods, for example heating in the presence of a base e.g. sodium hydroxide, and the racemic salt obtained optionally by crystallisation or by evaporation, recycled by carrying out steps a) to e) above.
Suitably racemic sodium 2-(4-isobutylphenyl)-propionate is used in the process. It may be prepared by hydrolysis of an ester of 2-(4-isobutylphenyl)-propionic acid or by hydrolysis of 2-(4-isobutylphenyl)-propionitrile or by hydrolysis of a 2-(4-isobutylphenyl) propionamide derivative or by other methods known to those skilled in the art.
Suitably any solvent or mixture of solvents, in which sodium 2-(4-isobutylphenyl)propionate is soluble and from which the salt may be recovered by crystallisation, may be employed. Suitably a mixture of water and a partially water miscible organic solvent for example methyl ethyl ketone may be used. Preferably, the solvent is a mixture of water and at least one water-miscible solvent selected from acetone or a C1-4 alcohol for example methanol, ethanol, propan-1-ol, propan-2-ol or butan-1-ol. Most preferably the solvent comprises a mixture of water and acetone.
In a further aspect of the present invention the S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate obtained by any of the above processes may be acidified to produce S(+)-ibuprofen having an increased enantiomeric purity compared to that of the 2-(4-isobutylphenyl)-propionic acid used initially. This process is commercially extremely useful since S(+)-ibuprofen may be prepared by resolution of the racemic acid as described earlier or by asymmetric synthesis using chemical techniques, for example asymmetric hydrogenation, or biochemical techniques, for example stereoselective enzymatic ester hydrolysis. In such methods the final purification step is often a problem if the enantiomeric purity of the material obtained is not of the required standard. Previously an expensive resolution would have been required to upgrade the enantiomeric purity to an acceptable level,for example to greater than 99% purity. The process herein described provides a cheap and efficient method of increasing the enantiomeric purity of S(+)-ibuprofen to produce S(+)-ibuprofen of 99% or greater enantiomeric purity.
In a similar manner we have found that the enantiomeric purity of R(xe2x88x92)-ibuprofen may be increased by conversion into R(+)sodium 2-(4-isobutylphenyl)-propionate using the same process.
As mentioned previously when the solvent system employed contains water in at least twice the stoichiometric amount of the 2-(4-isobutylphenyl)-propionic acid used as the starting material, S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate dihydrate is produced, which is novel.
Accordingly, the present invention provides S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate dihydrate having an enantiomeric purity of at least 90%. Preferably the enantiomeric purity of the S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate dihydrate is greater than 95% (that is 95-100%), more preferably the enantiomeric purity is greater than 98% and most preferably the enantiomeric purity of the S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate dihydrate is greater than 99%. In an especially preferred embodiment of the present invention the enantiomeric purity of the S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate dihydrate is greater than 99.5% e.g. greater than 99.9%.
The solid dihydrate compound flows freely and does not absorb further water. A particularly preferred embodiment of the present invention comprises solid S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate dihydrate in which two molecules of water are present for each molecule of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate.
In another aspect the present invention provides S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate for use in the treatment of inflammation, pain and pyrexia.
The invention is illustrated by the following non-limitative Examples.
The samples of S(+)-2-(4-isobutylphenyl)propionic acid used as the starting materials in the examples were prepared by resolving racemic ibuprofen using S(xe2x88x92)-1-phenylethylamine in a similar manner to that described in J. Pharm. Sci. 65 (1976) p.269-273. Acidification of the S(xe2x88x92)-1-phenylethylammonium S(+)-2-(4-isobutylphenyl)propionate salt initially produced gave S(+)-2-(4-isobutylphenyl)propionic acid of enantiomeric purity in the range 85-88%. Recrystallisation of the initially produced salt from propan-2-ol gave S(+)-2-(4-isobutylphenyl)propionic acid of enantiomeric purity in the range 95-99% after acidification.
The sample of R(xe2x88x92)-2-(4-isobutylphenyl)propionic acid used as a starting material was prepared by resolving racemic ibuprofen using R(+)-1-phenylethylamine in a similar manner to that described in J. Chromatography 99, (1974), p.541-551.
Enantiomeric Purity Determinations
The enantiomeric purity of samples of S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate was determined as follows. The S(xe2x88x92)sodium 2-(4-isobutylphenyl)propionate was acidified with 5 M hydrochloric acid and the mixture extracted with ether. The combined ether extracts were washed with water, dried and evaporated to give S(+)2-(4-isobutylphenyl)propionic acid.
This sample of S-(+)2-(4-isobutylphenyl)propionic acid was reacted with thionyl chloride and acetyl chloride to form S(+)-2-(4-isobutylphenyl)propionyl chloride which was then reacted with (xe2x88x92)-1-phenylethylamine to form N-(xe2x88x92)-1-phenylethyl-S(+)-2-(4-isobutylphenyl)propionamide. The amount of the diastereoisomeric amide formed from the R(xe2x88x92)-2-(4-isobutylphenyl)propionic present in each sample was determined using HPLC.